JP5937201B2 - 2-Amino-3- (imidazol-2-yl) pyridin-4-one derivatives and their use as VEGF receptor kinase inhibitors - Google Patents

Description

  The present invention relates to 7-phenol or 7-alkynyl-3- (imidazol-2-yl) -1,8-naphthyridin-4-one derivatives and their possible quinolinone analogs, which are inhibitors of the kinase activity of the VEGF receptor, It relates to its manufacture and its use as a therapeutic.

  The VEGF (vascular endothelial growth factor) family of proteins consists of three structurally related receptor tyrosine kinases called VEGF-R1 (Flt-1), VEGF-R2 (KDR) and VEGF-R3 (Flt-4) Combine with. All three receptors are essential for the development of vasculature during embryogenesis and tumor-induced angiogenesis. In addition, VEGFR-3 plays an important role in the development of the lymphatic system and tumor-induced lymphangiogenesis.

  In particular, WO 2009/007535 describes substituted 7-alkynyl-4-oxo-1,8-naphthyridine-3-carboxamide derivatives that are inhibitors of the kinase activity of the VEGF receptor. The compounds of the present invention differ from these prior art compounds in that they have an imidazole ring at least at the 3-position of the bicyclic system.

  Conditions to consider in the development of a drug compound are the tissue exposure of the compound and its efficacy. These conditions can be improved by improving at least one of efficacy, absorption, distribution, metabolism, excretion and toxicity.

International Publication No. 2009/007535

  There remains a need to obtain highly active inhibitors of VEGF receptor kinase activity, which is advantageously achieved by the novel compounds of the present invention.

  The first object of the present invention relates to a compound corresponding to the following general formula (I).

  Another subject of the present invention relates to a process for the preparation of compounds of general formula (I).

  Another subject of the present invention relates in particular to the use of a compound of general formula (I) in a medicament or pharmaceutical composition.

  The compounds of the present invention have the general formula (I):

に対応し、式中、
−Ｗは窒素原子又はＣＨ基を表し；
−Ｙは１個以上のハロゲン原子を表すＲ_７で場合により置換された、Ｃ_２−Ｃ_３アルキニレン基、１，４−フェニレン基を表し；
−Ｚは結合又はＣＲ_１Ｒ_２基を表し；
−Ｒ_１及びＲ_２は相互に独立して場合により１個以上のハロゲン原子で置換された、水素原子、Ｃ_１−Ｃ_６アルキル基、トリフルオロメチル基、（ＣＨ_２）_ｎＯＲ_６基、Ｃ_３−Ｃ_７シクロアルキル基、ヘテロアリール基もしくはアリール基から選択される基を表し；
−Ｒ_１及びＲ_２はそれらを担持している炭素原子と一緒になってＣ_３−Ｃ_７シクロアルキル基を形成してもよく；
−Ｒ_３は水素原子を表し；
−Ｒ_４は場合によりＣ_３−Ｃ_７シクロアルキル基で置換された、Ｃ_１−Ｃ_６アルキル基、（ＣＨ_２）_ｎＯＲ_６基、Ｃ_３−Ｃ_７シクロアルキル基又はＣ_１−Ｃ_６アルキル基から選択される基を表し；
−Ｒ_５は水素原子又はＣ_１−Ｃ_６アルキル基から選択される基を表し；
−Ｒ_６は水素原子又はＣ_１−Ｃ_６アルキル基から選択される基を表し；
−ｎは１、２又は３である。

In the formula,
-W represents a nitrogen atom or a CH group;
-Y is optionally substituted with _{R 7} representing a 1 or more halogen _atom, C 2 -C ₃ alkynylene group, a 1,4-phenylene group;
-Z represents a bond or a CR ₁ R ₂ group;
-R ₁ and R ₂ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group, a trifluoromethyl group, a (CH ₂ ) _n OR ₆ group, optionally substituted with one or more halogen atoms, C ₃ -C ₇ cycloalkyl group, represents a group selected from heteroaryl or aryl group;
-R ₁ and R ₂ together with the carbon atom carrying them may form a C ₃ -C ₇ cycloalkyl group;
-R ₃ represents a hydrogen atom;
-R ₄ are substituted by _C 3 -C ₇ cycloalkyl group _optionally, C 1 -C _{6 alkyl, (CH 2)} n OR _{6 group,} C 3 -C ₇ cycloalkyl group or a _C 1 -C ₆ Represents a group selected from alkyl groups;
-R ₅ represents a group selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
-R ₆ represents a group selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
-N is 1, 2 or 3.

  The compound of formula (I) may contain one or more asymmetric carbon atoms. Thus, the compounds may exist as enantiomers or diastereomers. These enantiomers and diastereomers and mixtures thereof including racemic mixtures are also included in the present invention.

  The compound of formula (I) may exist as a base or may exist as an acid addition salt. Such addition salts are also included in the present invention.

  These salts can be prepared using pharmaceutically acceptable acids, but other acid salts useful, for example, for purifying or isolating compounds of formula (I) are also included in the invention.

For the present invention, the following definitions apply:
-Halogen atom: A fluorine, chlorine, bromine or iodine atom.
-C _t -C _z: a possible carbon chain number t of z carbon atoms, t and z can take values from 1 to 7, for _example, C 1 -C ₃ Possible 1 -C To 3 carbon chains.
-Alkyl: linear or branched saturated aliphatic group. Examples include methyl group, ethyl group, n-propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group and the like.
- alkylene: derived by each removal of a hydrogen atom by one to two terminal carbon atoms of the alkane chain, optionally a divalent group substituted by an alkyl group, for example C ₁ -C ₃ alkylene group A linear or branched divalent carbon chain having 1 to 3 carbon atoms is represented, and more specifically, a methylene group, an ethylene group, a methylethylene group, or a propylene group can be mentioned.
Alkenylene: a divalent group derived by removing one hydrogen atom from each of the two terminal carbon atoms of the alkene chain and optionally substituted with an alkyl or alkenyl group, for example C ₂ -C ₃ The alkenylene group represents a straight or branched divalent carbon chain having 2 to 3 carbon atoms, and more specifically includes an ethenylene group or a propenylene group.
-Alkynylene: a divalent group derived by removing one hydrogen atom from each of the two terminal carbon atoms of the alkyne chain and optionally substituted with an alkyl, alkenyl or alkynyl group, for example C ₂ The —C ₃ alkynylene group represents a straight or branched divalent carbon chain having 2 to 3 carbon atoms, and more specifically includes an ethynylene group or a propynylene group.
-Cycloalkyl: a saturated or partially unsaturated cyclic alkyl group. Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group and the like.
-Cycloalkoxy: -O-cycloalkyl group, wherein the cycloalkyl group is as defined above.
-Fluoroalkyl: an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms.
-Alkoxy: an -O-alkyl group, wherein the alkyl group is as defined above.
-Fluoroalkoxy: an alkoxy group in which one or more hydrogen atoms are replaced by fluorine atoms.
-Thioalkyl or alkylthio: -S-alkyl group, wherein the alkyl group is as defined above.
-Aryl: monocyclic or bicyclic aromatic group having 6 to 10 carbon atoms. Examples of the aryl group include a phenyl group and a naphthyl group.
-Arylene: A divalent group derived by removing one hydrogen atom of two ring carbon atoms from aryl. An example of an arylene group is a phenylene group.
-Heterocycle: a saturated or partially unsaturated 5- to 7-membered monocyclic group containing 1 to 3 heteroatoms selected from O, S and N. Examples of heterocycles include azetidinyl, piperidyl, azepinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, dihydrooxazolyl, dihydrothiazolyl, dihydroimidazolyl, dihydropyrrolyl or tetrahydropyridyl, [1,3] dioxolyl, [1, 3] Dioxinyl, dihydro [1,4] dioxinyl, dihydro [1,2] oxazinyl, dihydro [1,3] oxazinyl, dihydrooxazolyl, dihydroisoxazolyl, dihydro [1,4] oxazinyl, tetrahydro [1 , 3] oxazepinyl, tetrahydro [1,4] oxazepinyl, tetrahydro [1,3] diazepinyl and tetrahydro [1,4] diazepinyl.
-Heteroaryl: a 5- to 12-membered monocyclic or bicyclic aromatic group containing 1 to 5 heteroatoms selected from O, S and N. Examples of monocyclic heteroaryl include imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, furyl, thienyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl. Examples of bicyclic heteroaryl include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzoxazolyl, benzimidazolyl, indazolyl, benzothienyl, isobenzofuryl, isobenzothiazolyl, pyrrolo [2,3-c] Pyridyl, pyrrolo [2,3-b] pyridyl, pyrrolo [3,2-b] pyridyl, pyrrolo [3,2-c] pyridyl, pyrrolo [1,2-a] pyridyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, Quinoxalinyl, pyrrolo [1,2-a] imidazolyl, imidazo [1,2-a] pyridyl, imidazo [1,2-a] pyridazinyl, imidazo [1,2-c] pyrimidinyl, imidazo [1,2-a] Pyrimidinyl, imidazo [1,2-a] pyrazinyl, imidazo [4,5-b] pyrazinyl, Midazo [4,5-b] pyridyl, imidazo [4,5-c] pyridyl, pyrazolo [2,3-a] pyridyl, pyrazolo [2,3-a] pyrimidinyl, pyrazolo [2,3-a] pyrazinyl, Thiazolo [5,4-b] pyridyl, thiazolo [5,4-c] pyridyl, thiazolo [4,5-c] pyridyl, thiazolo [4,5-b] pyridyl, oxazolo [5,4-b] pyridyl, Oxazolo [5,4-c] pyridyl, oxazolo [4,5-c] pyridyl, oxazolo [4,5-b] pyridyl, isothiazolo [5,4-b] pyridyl, isothiazolo [5,4-c] pyridyl, Isothiazolo [4,5-c] pyridyl, isothiazolo [4,5-b] pyridyl, isoxazolo [5,4-b] pyridyl, isoxazolo [5,4-c] pyridyl, isoxazolo [ , 5-c] pyridyl, and isoxazolo [4,5-b] include pyridyl.
“Oxo” means “═O”.
-"Thio" means "-S-".

For the present invention, the following abbreviations and formulas are used.
Boc tert-Butyloxycarbonyl CuI Copper iodide (I)
CH ₂ Cl ₂ dichloromethane HPLC high performance liquid chromatography LC / MS liquid chromatography mass spectrometry dba dibenzylideneacetone DCM dichloromethane DME dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide dppf 1,1′-bis (diphenylphosphino) ferrocene ° C. Et ₃ N triethylamine h time HCl hydrochloric acid IR infrared MeOH methanol min. Minute ml Milliliter MgSO ₄ Magnesium sulfate NaCl Sodium chloride NH ₄ Cl Ammonium chloride NH ₄ OH Ammonium hydroxide NaHCO ₃ Sodium bicarbonate Na ₂ SO ₄ Sodium sulfate NMR Nuclear magnetic resonance Rt Retention time SEM [2- (Trimethylsilyl) ethoxy] methyl THF Tetrahydrofuran TOSMIC Tosylmethyl isocyanide trityl triphenylmethyl Xphos 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl.

  Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the first subgroup are constituted by compounds in which W represents a nitrogen atom or a CH group.

  Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the second subgroup are composed of compounds in which W represents a nitrogen atom.

Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the third subgroup are constituted by compounds in which Y represents a C ₂ -C ₃ alkynylene group, more specifically an ethynylene group.

Of the compounds of general formula (I) that are the subject of the present invention, compounds of the fourth subgroup are:
-Z represents a bond, a CR ₁ R ₂ group;
—R ₁ optionally substituted with one or more halogen atoms, a hydrogen atom, a C ₁ -C ₆ alkyl group, a (CH ₂ ) _n OR ₆ group, a C ₃ -C ₇ cycloalkyl group, an aryl group or 5 Represents a group selected from a membered or 6-membered heteroaryl group;
-R ₂ represents a group selected from hydrogen _atom, C 1 -C ₆ alkyl or trifluoromethyl groups;
Represents a group -R ₆ are selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.

Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the fifth subgroup are:
-Z represents a CR ₁ R ₂ group;
-R ₁ is hydrogen _atom, C 1 -C _{6 alkyl,} a _{(CH 2)} n OR _{6 group,} C 3 -C ₇ cycloalkyl group, an aryl group or a 5-membered or 6-membered group selected from a heteroaryl group Representation;
-R ₂ represents a group selected from hydrogen _atom, C 1 -C ₆ alkyl or trifluoromethyl groups;
Represents a group -R ₆ are selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.

Y is _C 2 -C ₃ alkynylene group, when more specifically representing the ethynylene group, Z is represents _CR 1 _{R 2} group, _{R 1} and _{R 2} are as defined above.

Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the sixth subgroup are C ₁ -C ₆ alkyl groups, wherein R ₄ is optionally substituted by a C ₃ -C ₇ cycloalkyl group , (CH ₂ ) _n OR ₆ group, C ₃ -C ₇ cycloalkyl group or C ₁ -C ₆ alkyl group.

Among the compounds of the general formula (I) that are the subject of the present invention, the compounds of the seventh subgroup are composed of compounds in which R ₄ represents a C ₁ -C ₆ alkyl group, more specifically an ethyl group. .

Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the eighth subgroup are constituted by compounds in which R ₅ represents a group selected from a hydrogen atom or a _1- C ₆ alkyl group.

Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the ninth subgroup are composed of compounds in which R ₅ represents a hydrogen atom.

Among the compounds of general formula (I) that are the subject of the present invention, the compounds of the tenth subgroup are composed of compounds that combine the above definitions of W, Y, Z, R ₃ , R ₄ and R ₅ .

Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the eleventh subgroup
-W represents a nitrogen atom or a CH group;
-Y is substituted with a halogen atom optionally _represents a C 2 -C ₃ alkynylene group or a 1,4-phenylene group;
-Z represents a bond, a CR ₁ R ₂ group;
—R ₁ optionally substituted with a halogen atom, a hydrogen atom, a C ₁ -C ₆ alkyl group, a (CH ₂ ) _n OR ₆ group, a C ₃ -C ₇ cycloalkyl group, an aryl group, or a 5 or 6 member Represents a group selected from heteroaryl groups;
-R ₂ represents a group selected from hydrogen _atom, C 1 -C ₆ alkyl or trifluoromethyl groups;
-R ₃ is hydrogen;
-R ₄ is substituted with a _C 3 -C ₇ cycloalkyl group _optionally, C 1 -C _{6 alkyl, (CH 2)} n OR _{6 group,} C 3 -C ₇ cycloalkyl group or a _C 1 -C ₆ Represents a group selected from alkyl groups;
-R ₅ are radicals represents a group selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
Represents a group -R ₆ are selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.

Of the compounds of general formula (I) that are the subject of the present invention, the compounds of the twelfth subgroup are:
-W represents a nitrogen atom or a CH group;
-Y represents a _C 2 -C ₃ alkynylene group;
-Z represents a CR ₁ R ₂ group;
—R ₁ optionally substituted with a halogen atom, a hydrogen atom, a C ₁ -C ₆ alkyl group, a (CH ₂ ) _n OR ₆ group, a C ₃ -C ₇ cycloalkyl group, an aryl group, or a 5 or 6 member Represents a group selected from heteroaryl groups;
-R ₂ represents a group selected from hydrogen _atom, C 1 -C ₆ alkyl or trifluoromethyl groups;
-R ₃ is hydrogen;
-R ₄ is substituted with a _C 3 -C ₇ cycloalkyl group _optionally, C 1 -C _{6 alkyl, (CH 2)} n OR _{6 group,} C 3 -C ₇ cycloalkyl group or a _C 1 -C ₆ Represents a group selected from alkyl groups;
-R ₅ are radicals represents a group selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
Represents a group -R ₆ are selected from hydrogen atom or a _C 1 -C ₆ alkyl group;
It is constituted by a compound in which n is 1, 2 or 3.

Of the compounds of general formula (I) that are the subject of the present invention, compounds of the thirteenth subgroup are those in which R ₁ and R ₂ together with the carbon atom carrying them are C ₃ -C ₇ cyclo It is comprised by the compound which forms an alkyl group.

  Of course, each of the above subgroups may be combined with one or more of the other subgroups, and the corresponding compounds are also the subject of the present invention.

Among the compounds of the general formula (I) that are the subject of the present invention, the following compounds can be mentioned in particular.
1: 2-amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1 , 8] naphthyridin-4-one 2: 2-amino-1-propyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazole-2 -Yl) -1H- [1,8] naphthyridin-4-one 3: 2-amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazole) -2-yl) -1H- [1,8] naphthyridin-4-one 4: 2-amino-1-ethyl-7- (3-hydroxy-3-pyridin-2-ylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1, ] Naphthyridin-4-one 5: 2-amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- (4-methyl) -1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 6: 2-amino-1- (cyclopropylmethyl) -7- (3-hydroxypent-1-yne-1- Yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 7: 2-amino-1-ethyl-7-[(3R) -3-hydroxy-4- Methoxy-3-methylbut-1-in-1-yl] -3- (1H-imidazol-2-yl) quinolin-4 (1H) -one 8: 2-amino-7- (3-chloro-4-hydroxy Phenyl) -1-ethyl-3- (1H-imidazo -2-yl) -1,8-naphthyridin-4 (1H) -one 9: 2-amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-yne-1 -Yl] -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 10: 2-amino-1-cyclopentyl-7- (3-hydroxypent-1-yne- 1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 11: 2-amino-7- (3-hydroxypent-1-yn-1-yl ) -3- (1H-imidazol-2-yl) -1- (3-methoxypropyl) -1,8-naphthyridin-4 (1H) -one 12: 2-amino-7- (3-hydroxypenta-1 -In-1-yl) -3- (1H-imidazole- 2-yl) -1- (2-methoxyethyl) -1,8-naphthyridin-4 (1H) -one 13: 2-amino-1-ethyl-7-[(1-hydroxycyclobutyl) ethynyl] -3 -(1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 14: 2-amino-1-ethyl-7-[(1-hydroxycyclopentyl) ethynyl] -3- (1H- Imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 15: 2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-in-1-yl) -3 -(1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 16: 2-amino-1-ethyl-7- (3-hydroxy-3-methylpent-1-yne-1- Il) -3- (1H-imidazo Ru-2-yl) -1,8-naphthyridin-4 (1H) -one 17: 2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-in-1-yl)- 3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 18: 2-amino-1-ethyl-7- [3- (3-fluorophenyl) -3-hydroxybuta -1-In-1-yl] -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 19: 2-amino-1-ethyl-3- (1H-imidazole) -2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-in-1-yl) -1,8-naphthyridin-4 (1H) -one 20: 2-Amino-7- (3-cyclopropyl-3-hydroxybuta- -In-1-yl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 21: 2-amino-1-ethyl-7- [3 -Hydroxy-3- (thiophen-2-yl) but-1-in-1-yl] -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 22: 2 -Amino-1-ethyl-7- (3-hydroxybut-1-yn-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 23: 2-Amino-1-ethyl-7- (3-hydroxypent-1-yn-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 24 : 2-amino-1-ethyl-7- (3-hydroxyhex-1-y N-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 25: 2-amino-1-ethyl-7- (3-hydroxy-4- Methylpent-1-in-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 26: 2-amino-1-ethyl-7- (3- Hydroxy-3-phenylprop-1-in-1-yl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 27: 2-amino-7-(( 3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 28: 2- Amino-7-((3S) -3,4-dihydroxy-3-methyl Rubut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 29: 2-amino-1-ethyl-7-((3S ) -3-Hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one.

  In the text below, the term “leaving group” means a group that can be easily cleaved from a molecule by breaking a heterogeneous bond and losing an electron pair. Thus, this group can be easily replaced with another group, for example during a substitution reaction. Such leaving groups are, for example, activated hydroxyl groups such as halogen, methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate and the like. For examples of leaving groups and a description of their preparation, see “Advanceds in Organic Chemistry”, J. Am. See March, 5th Edition, Wiley Interscience, 2001.

  In the text below, the term “protecting group” (PG) can be temporarily introduced into a chemical structure for the purpose of temporarily deactivating a portion of the molecule during the reaction, and can be easily used in subsequent synthetic steps. Means a group which can be removed. For examples of protecting groups and a description of their properties, see “Protective Groups in Organic Synthesis”, T.W. W. Greene, P.M. G. M.M. See Wutz, 3rd Edition, Wiley Interscience 1999.

  According to the present invention, compounds of general formula (I) can be prepared according to the methods shown in the following general schemes 1, 2 and 3.

According to Scheme 1, in step (i), a protic solvent such as alcohol (eg, ethanol, n-butanol, tert-butanol) or water at room temperature or at a temperature of 50 ° C. to 100 ° C. by normal heating or microwave heating. In which the 2-position of 2,6-dihalogenonicotinic acid of formula (II) is an amine of formula R ₄ —NH ₂ , wherein R ₄ is as defined above for the compound of formula (I) Mono-substitution. The acid (III) obtained from step (i) is then prepared according to step (ii) according to G. As described by Olah et al. In Synthesis (1973), 487, acid fluorides by the action of cyanuric fluoride in an aprotic solvent such as dichloromethane or THF at room temperature in the presence of a base such as triethylamine or pyridine. Or as an imidazolide by the action of carbonyldiimidazole in a polar aprotic solvent such as DMF or THF, or by Mukaiyama and Tanaka, Chem. Lett. (1976), 303 or Ishikawa and Sasaki, Chem. Lett. (1976), 1407, and other methods known to those skilled in the art to obtain the derivative of formula (IV).

  The cyanomethylimidazole of formula (V) is prepared in two steps from imidazole-2-carboxaldehyde which is unsubstituted or substituted at the (4,5) position of imidazole. In step (iii), for example, “Protective Groups in Organic Synthesis”, Greene et al. Protecting the free nitrogen of imidazole-2-carboxaldehyde with PG in Scheme 1 under normal operating conditions known to those skilled in the art, as described in, 3rd Edition (John Wiley & Sons, Inc., New York) Protected by a group (eg SEM group, Boc group or trityl group). When appropriate, two isomers of protected imidazole, τ and π, are obtained and used indiscriminately in subsequent reactions. Next, in step (iv), the anion of TOSMIC formed by adding potassium tert-butyrate to an anhydrous DSM solution of TOSMIC at a low temperature (−50 ° C.) is reacted with the aldehyde functional group, and then the formed anion. Ring opening of 4-tosyl-2-oxazoline, which is a functional intermediate, followed by Van Leusen A. et al. (Synthetic Comm, 10 (5) 1980, 399-403), the reaction mixture is heated to reflux in the presence of methanol to form the acetyl nitrile functional group, thereby protecting the protected imidazole-2- Carboxaldehyde is converted to cyanomethylimidazole of formula (V).

  The oxyfluoride or imidazolide of formula (IV) obtained after step (ii) is very reactive but stable, which is then converted in step (v) such as sodium hydride or potassium tert-butoxide. Reaction with an unsubstituted or (4,5) -substituted cyanomethylimidazole of the formula (V) in a polar aprotic solvent such as THF or DMF at a temperature from −5 ° C. to room temperature in the presence of 1 equivalent of a base. Then, another equivalent of the base used previously is added, and the formed compound of formula (VI) is cyclized in situ at room temperature according to step (vi) to obtain the pyridino-pyridinone compound of formula (VII).

According to Scheme 2, in step (vii), potassium permanganate in the presence of a base such as pyridine in a protic solvent such as water at room temperature or a temperature of 50 to 100 ° C. by normal heating or microwave heating. The 2,4-dihalogenotoluene of formula (VIII) can be obtained by using a strong oxidizing agent such as, for example, or by other methods known to those skilled in the art, such as the method described in US Pat. No. 6,187,950. Oxidize to the corresponding acid derivative (IX). Alcohol (eg, ethanol, n-butanol, tert-butanol) or water at the 2-position of the acid (IX) obtained from step (vii) at room temperature or a temperature of 50 ° C. to 100 ° C. by normal heating or microwave heating Mono-substituted with an amine of formula R ₄ —NH _{2 where} R ₄ is as defined above for compounds of formula (I) in a protic solvent such as The acid (X) obtained from step (viii) is then carbonylated in an aprotic solvent such as DMF, toluene, THF, dioxane or the like at room temperature or at a temperature of 50 ° C. to 120 ° C. by normal heating or microwave heating. It is cyclized by the action of diimidazole or triphosgene to give benzo-1,3-oxazine-2,4-dione (XI). Next, benzo-1,3-oxazine-2,4-dione (XI) is added to DMF at room temperature in the presence of a base such as triethylamine or pyridine at a temperature of 50 ° C. to 120 ° C. by normal heating or microwave heating. Treatment with malononitrile in an aprotic solvent such as toluene, dioxane or other methods known to those skilled in the art, such as the method described in Synthesis (2008) 1535 by Iminov et al. Provides nitrile (XII). The nitrile (XII) obtained from the step (x) is DME, DMF, toluene, dioxane, etc. at room temperature or a temperature of 50 to 120 ° C. by ordinary heating or microwave heating in the presence of a copper catalyst such as CuCl. Is reacted with aminoacetaldehyde diethyl acetal in an aprotic solvent. The acetal (XIII) obtained from the step (xi) is then alcohol (eg ethanol, n-butanol, tert-butanol), water, etc. at room temperature or at a temperature of 50 ° C. to 120 ° C. by normal heating or microwave heating. Was cyclized into imidazole (XIV) using strongly acidic conditions such as HCl (12N) in a protic solvent.

  To obtain the compounds of formula (I) of the present invention, two methods shown in Scheme 3 can be used starting from halogenated intermediates of formula (VII) or (XIV).

According to a first method for obtaining a compound of formula (I) which is the subject of the present invention, in step (xiii), propargyl alcohol R ₁ R ₂ CH (OR ₃ ) C≡CH of formula (XVa) Wherein R ₁ , R ₂ and R ₃ are as defined above) in a Sonogashira coupling reaction with a suitable derivative or a Suzuki coupling reaction with a suitable arylboronic acid of formula (XVb) VII) or (XIV) halogenated intermediates are used. Sonogashira reaction (xiii) is carried out in the presence of palladium complex (in oxidation state (0) or (II)) such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , copper iodide, triethylamine The reaction is carried out in an aprotic polar solvent such as THF and DMF under normal heating at 120 to 120 ° C. or microwave heating.

Suzuki reaction (xiii) is a palladium complex (of oxidation state (0) or (II)) such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ dba ₃ , Xphos or PdCl ₂ (dppf). And DME, ethanol, DMF, dioxane or these under normal heating at 80 to 120 ° C. or microwave heating at 130 to 170 ° C. in the presence of a base such as cesium carbonate, aqueous sodium hydrogen carbonate or K ₃ PO ₄ It is carried out in a protic or aprotic polar solvent such as a mixture of the above solvents.

  The Shantou (XVIa) or Suzuki (XVIb) reaction product is finally subjected to −5 ° C. to 60 ° C. in the presence of a dioxane or trifluoroacetic acid solution of an acid such as HCl (4N) according to the usual deprotection step (xiv) The compound of formula (I) is obtained by deprotection in a solvent such as ethanol or dichloromethane at the temperature of

According to the second method for obtaining the compound of formula (I) which is the subject of the present invention, first the halogenated intermediate of formula (VII) or (XIV) is prepared according to the same general procedure as in step (xiv). Deprotect (xv). The resulting unprotected compound (XVII) is treated with propargyl alcohol R ₁ R ₂ CH (OR ₃ ) C≡CH (XVa) (wherein R ₁ , R ₁ ) according to the same conditions as described above for step (xiii) ₂ and R ₃ are as defined above) in a Sonogashira coupling reaction with a suitable derivative or a Suzuki coupling reaction with a suitable arylboronic acid of formula (XVb). Both coupling reactions give compound (I) directly.

If necessary, during the reaction step shown in Scheme 1, hydroxyl groups or certain reactive functional groups present on the R ₁ , R ₂ and R ₃ groups can be added to “Protective Groups in Organic Synthesis”, Greene et al. , 2nd Edition (John Wiley & Sons, Inc., New York), may be temporarily protected with a protecting group known to those skilled in the art.

  According to another aspect, compounds of formula (VII) as described in Scheme 1 are also subject of the present invention. These compounds can be used as synthetic intermediates for compounds of formula (I).

  According to another aspect, formula (VII):

［式中、Ｘは塩素又は臭素であり、Ｒ_４及びＲ_５は一般式（Ｉ）に定義した通りである］の化合物を一般式（ＸＶａ）：

[Wherein X is chlorine or bromine, and R ₄ and R ₅ are as defined in general formula (I)], a compound of general formula (XVa):

［式中、Ｒ_１、Ｒ_２及びＲ_３は一般式（Ｉ）に定義した通りである］の化合物と反応させるか、
又は一般式（ＸＶｂ）：

In which R ₁ , R ₂ and R ₃ are as defined in general formula (I), or
Or general formula (XVb):

［式中、Ｒ_３及びＲ_７は一般式（Ｉ）に定義した通りである］の化合物と反応させ、
式（ＶＩＩ）の化合物を一般式（ＸＶａ）の化合物又は一般式（ＸＶｂ）の化合物と反応させる前又は後に通常の脱保護工程を実施することを特徴とする、式（Ｉ）の化合物の製造方法も本発明の対象である。

In which R ₃ and R ₇ are as defined in general formula (I);
Preparation of a compound of formula (I), characterized in that a usual deprotection step is carried out before or after reacting a compound of formula (VII) with a compound of general formula (XVa) or a compound of general formula (XVb) The method is also the subject of the present invention.

  The following examples describe the preparation of certain compounds of the present invention. These examples are not limiting and merely illustrate the invention. The specified compound numbers correspond to the numbers shown in Table 1. The structure of the obtained compound is confirmed by trace element analysis, LC / MS analysis and IR or NMR spectrum.

Example 1: (Compound No. 1)
2-Amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 ] -Naphthyridin-4-one

1.1: 6-chloro-2-ethylaminonicotinic acid A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of a solution of ethylamine (70% aqueous solution) at ambient temperature for 72 hours Stir. The excess amine was then evaporated under reduced pressure and 10% aqueous acetic acid was added until the product precipitated. The beige solid was dehydrated with a spin filter, rinsed with cold water and oven dried. 10.5 g of the expected product is obtained.
Melting point = 158-160 ° C.
Yield = 62%.

1.2: 6-Chloro-2-ethylaminonicotinoyl fluoride 6 ml of 6-chloro-2-ethylaminonicotinic acid (24.8 mmol) was suspended in 125 ml of dichloromethane in 2 ml of pyridine (24.24). 8 mmol) and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine were added. The mixture was stirred at ambient temperature for 3 hours and then filtered. The solid was rinsed with 50 ml of dichloromethane and the filtrate was washed twice with 60 ml of ice cold water. The organic phase was dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. 5.01 g of product was obtained as an orange oil and used without further purification.
Yield = 99%.

1.3: 1- (2-Trimethylsilanylethoxymethyl) -1H-imidazole-2-carbaldehyde An oily suspension obtained by suspending 20.8 g of sodium hydride in mineral oil (50%, 0.52 mol) The mineral oil was washed away with hexane three times under stirring, and suspended in 400 ml of DMF. Under stirring at ambient temperature, 50.0 g (0.520 mol) of imidazole-2-carbaldehyde was added to the suspension. After 1.5 hours, 101.0 ml (0.572 mol) of 2- (trimethylsilanyl) ethoxymethyl chloride was added and the reaction mixture was stirred for an additional hour. Excess water was then added to the suspension and the reaction mixture was extracted three times with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was then purified by column chromatography (DCM) to give 85.0 g (0.376 mol) of SEM protected imidazole-2-carbaldehyde. .
Yield = 72%.
_{MH + = 227.1 (C 10 H} 18 N 2 O 2 Si, Mr = 226.35).
1H NMR (DMSO-d6,500 MHz): δ 9.83 (s, 1H); 7.86 (s, 1H); 7.39 (s, 1H); 5.75 (s, 2H); 3.58 ( t, 2H); 0.95 (t, 2H); 0.02 (s, 9H).

1.4: [1- (2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] acetonitrile 1.73 g (8.84 mmol) of tosylmethyl isocyanide was dissolved in 10 ml of DME and cooled to −60 ° C. First, 1.98 g of potassium tert-butoxide was added at this temperature, and then 2.00 g (8.84 mmol) of 1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carbaldehyde was dissolved in 5 ml of DME. Was added slowly. After stirring at −60 ° C. for 2 hours, the reaction mixture was raised to 0 ° C. and 5 ml (123.60 mmol) of methanol was added to the solution. The reaction mixture was stirred at ambient temperature for a further 24 hours and at 40 ° C. for 2 hours. Excess water was added and the solution was extracted three times with dichloromethane. After drying the organic phase with Na ₂ SO ₄ and evaporating the solvent under reduced pressure, the crude product was purified by reverse phase column chromatography (0.1% aqueous TFA solution / acetonitrile = 80/20) and SEM protected imidazole-acetonitrile 0. Obtained .87 g (0.367 mol).
Yield = 41%.
_{MH + = 238.1 (C 11 H} 19 N 3 OSi, Mr = 237.38).
1H NMR (DMSO-d6,500 MHz): δ 7.66 (s, 1H); 7.39 (s, 1H); 5.53 (s, 2H); 4.52 (s, 2H); 3.55 ( t, 2H); 0.92 (t, 2H); 0.02 (s, 9H).

1.5: 3- (6-Chloro-2-ethylaminopyridin-3-yl) -3-hydroxy-2- [1- (2- (trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] Acrylonitrile [1- (2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] acetonitrile (0.600 g, 2.53 mmol) dissolved in anhydrous THF (10 ml) at 0 ° C. with 0.283 g of potassium tert-butylate (2 The mixture was stirred at ambient temperature for 45 minutes and then cooled again to 0 ° C. Next, 0.512 g (2.53 mmol) of 6-chloro-2-ethylaminonicotinoyl fluoride was added. A solution dissolved in 10 ml of THF is added and the mixture is stirred overnight at ambient temperature, cooled again to 0 ° C. 1 equivalent (0.283 g, 2.53 mmol) of tert-butylate was added, and after stirring at ambient temperature for 2 hours, 50 ml of saturated aqueous ammonium chloride solution was added, the pH was adjusted to 7 with 2N HCl, and then 3 with ethyl acetate. The combined organic phases were dried over MgSO ₄ and the solvent was evaporated under reduced pressure The crude product was further purified by column chromatography (DCM / methanol = 90: 10) to give 418 mg of the title compound (Yield = 38%) as an intermediate and used in the next step.
_{MH + = 421 (C 19 H} 26 ClN 5 O 2 Si, Mr = 419.99).
1H NMR (DMSO-d6,500 MHz): δ 13.35 (s, 1H); 7.70 (d, 1H); 7.46 (s, 1H); 7.23 (s, 1H); 7.08 ( 6.58 (d, 1H); 5.59 (s, 2H); 3.58 (t, 2H); 3.34 (dq, 2H); 1.13 (t, 3H); -0.03 (3s, 9H).

1.6: 2-amino-7-chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridine-4 Intermediate 3- (6-Chloro-2-ethylaminopyridin-3-yl) -3-hydroxy-2- [1- (2- (trimethylsilanylethoxymethyl) -1H- prepared in 1.5 0.112 g (1 mmol) of potassium tert-butyrate was added in small portions to a low temperature solution of 418 mg (1 mmol) of imidazol-2-yl] acrylonitrile in 5 ml of anhydrous THF at 0 ° C. After the mixture was stirred at ambient temperature for 48 hours, 50 ml of saturated aqueous ammonium chloride solution was added, the pH was adjusted to 7 with 2N HCl and the reaction mixture was extracted three times with ethyl acetate. Dried SO _4, the solvent is evaporated under reduced pressure to give the title compound 400 mg.
Yield = 38%.
_{MH + = 421 (C 19 H} 26 ClN 5 O 2 Si, Mr = 419.99).
1H NMR (DMSO-d6,500 MHz): δ 8.50 (d, 1H); 8.03 (s, 1H); 7.98 (s, 1H); 7.78 (s, 2H); 7.60 ( 5.49 (s, 2H); 4.58 (q, 2H); 3.57 (t, 2H); 1.42 (t, 3H); 0.85 (t, 2H); -0.03 (3s, 9H).

1.7: (±) -2-methylbut-3-in-1,2-diol A 0.5 M tetrahydrofuran solution of commercially available ethynylmagnesium chloride was diluted with 200 ml of tetrahydrofuran and cooled to 0 ° C. A solution of hydroxyacetone in 200 ml of tetrahydrofuran was then added and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was cooled and aqueous NH ₄ Cl was added. The mixture was extracted three times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure (ca. 200 mbar). Finally, 20 g of the expected product was obtained as a brown oil (quantitative crude yield), used as a racemate without further purification, but separated into pure enantiomers by preparative HPLC on a chiral HPLC column. I was able to. To obtain an optically pure enantiomer, the mobile phase is CO ₂ / 2-propanol (70% / 30%) at a flow rate of 60 ml / min under a pressure of 100 bar or isohexane / ethanol (70% / min at a flow rate of 120 ml / min). The corresponding racemic mixture was subjected to preparative chromatography on a chiral stationary phase (Chiralpak AD-H column, 250 × 21 mm, 5 mm) using a 70/30) mixture + 0.3% TFA.

  Each enantiomer was isolated after elution and evaporation and the chemical and enantiomeric purity of each was determined by analytical methods known to those skilled in the art.

1.8: 2-Amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one Into an argon-substituted microwave reaction flask was added 2-amino-7-chloro-1-ethyl-3- [1- (2 -Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one 500 mg (1.2 mmol) and (3R) -1-methoxy-2-methylbuta-3 -In-2-ol 204 mg (1.8 mmol), bis (triphenylphosphine) palladium (II) dichloride 84 mg (0.120 mmol), copper (I) iodide 30 m g (0.16 mmol), 2 ml of DMF (degassed) and 2 ml of triethylamine (degassed) were charged, and microwave irradiation was performed so that the reaction mixture was maintained at 120 ° C. for 24 hours. The solvent was evaporated and the solid was resuspended in 3 ml DMF and filtered. The filtrate was then purified by HPLC to give 430 mg (0.702 mmol) of the TFA salt of the title compound.
Yield = 59%.
_{MH + = 498.2 (C 25 H} 35 N 5 O 4 Si, Mr = 497.67).
1H NMR (DMSO-d6,500 MHz): δ 8.39 (d, 1H); 7.95 (s, 1H); 7.88 (s, 1H); 7.60 (s, 2H); 7.48 ( d, 1H); 5.25 (s, 2H); 4.50 (broad signal, 2H); 3.52-3.40 (broad signal, water peak + 4H); 1.48 (s, 3H); 1 .25 (t, 3H); -0.12 (3 s, 9H).

1.9: 2-amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] Naphthyridin-4-one 1.8 SEM-protected naphthyridinone 240 mg (0.4 mmol) was dissolved in 1.2 ml TFA and 1.2 ml DCM at 0 ° C. The solution was maintained at 3-5 ° C. overnight until analytical HPLC showed complete deprotection of naphthyridinone. The solution was neutralized by adding excess aqueous NaHCO ₃ solution. The mixture was then extracted 3 times with ethyl acetate. The organic phases were combined and dried over MgSO ₄ and the solvent was evaporated under reduced pressure. The crude product thus obtained was purified on silica gel (DCM: MeOH = 4: 1) to give 143 mg (quantitative yield) of the unprotected title compound.
_{MH + = 368.2 (C 19 H} 21 N 5 O 3, Mr = 367.41).
1H NMR (DMSO-d6,500 MHz): δ 13.15 (s, 1H); 11.55 (bs, 1H); 8.59 (d, 1H); 8.10 (bs, 1H); 7.47 ( d, 1H); 7.25 (s, 1H); 7.02 (s, 1H); 5.85 (s, 1H); 4.58 (broad signal, 2H); 3.51-3.370 ( Broad signal, water peak + 4H); 1.48 (s, 3H); 1.25 (t, 3H).
Rt (analytical HPLC): 4.806 min.

Example 2: (Compound No. 2)
2-Amino-1-propyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 Naphthyridin-4-one Using n-propylamine instead of ethylamine in step 1.1 and using the procedure described up to step 1.6, 2-amino-7-chloro-1-propyl-3- [1- (2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one was synthesized. This intermediate was similarly coupled with (3R) -1-methoxy-2-methylbut-3-in-2-ol following the detailed procedure outlined in Example 1 to give the title compound.
_{MH + = 382.48 (C 20 H} 23 N 5 O 3, Mr = 381.44).
1H NMR (DMSO-d6,500 MHz): δ broad signal: 8.45 (m, 1H); 7.4 (m, 3H); 5.85 (s, 1H); 4.58 (m, 3H); 3.51-3.370 (water peak + 4H); 1.70 (m, 2H); sharp signal: 1.48 (s, 3H); 0.95 (t, 3H).
Rt (analytical HPLC): 4.98 min.

Example 3: (Compound Nos. 3, 27 and 28)
2-Amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridin-4 (1H) -one 2-Amino-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -one 2-amino-7-((3S) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8- Naphthyridine-4 (1H) -one

3.1: 2-Amino-1-ethyl-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H -Imidazol-2-yl] -1,8-naphthyridin-4 (1H) -one Intermediates described in 1.6 (2-amino-7-chloro-1-ethyl-3- [1- (2-trimethyl) Silanylethoxymethyl) -1H-imidazol-2-yl-1,8-naphthyridin-4 (1H) -one) and (±) -2-2 previously prepared according to the procedure described in Step 1.7 The title compound was obtained using methylbut-3-yne-1,2-diol following the detailed procedure outlined in step 1.8.
_{MH + = 354.16 (C 18 H} 19 N 5 O 3, Mr = 353.38).
Rt (analytical HPLC): 4.48 min.

3.2: 2-amino-1-ethyl-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxy) Methyl) -1H-imidazol-2-yl] -1,8-naphthyridin-4 (1H) -one 2-amino-1-ethyl-7-((3S) -3,4-dihydroxy-3-methylbuta-1 -Inyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1,8-naphthyridin-4 (1H) -one obtained in step 3.1. The resulting racemate was obtained by Berger preparative SFC, 230 nm UV detection, stationary phase Chiralpak IC 20 × 250 nm 5 μm, mobile phase 65% / 35% CO 2 /(MeOH+0.5% isopropylamine), 50 l / min, subjected to preparative Chiral SFC purification under the conditions of 100 bar, was separated into two enantiomers.

Berger SFC, 210 nm UV detection, stationary phase Chiralpak AD-H (250 mm × 4.6) 5 μm, mobile phase 65/35% CO 2 /(isopropanol+0.5% isopropylamine), 2.4 ml / min for the two enantiomers The optical purity was analyzed using the Chiral SFC method at 100 bar.
R-form (tr = 6.9 minutes, enantiomeric purity = 97.9%).
S form (tr = 5.9 minutes, enantiomeric purity = 96.8%).

3.3: 2-Amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -one 2-amino-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8- Naphthyridin-4 (1H) -one 2-amino-7-((3S) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl)- 1,8-naphthyridin-4 (1H) -one After the deprotection step according to step 1.9, compounds 3, 27 and 28 were isolated as yellow powders.
_{MH + = 354.16 (C 18 H} 19 N 5 O 3, Mr = 353.38).
Tr = 0.77 minutes.
1H NMR (DMSO-d6, 400 MHz): δ 13.15 (s, 1H); 11.55 (bs, 1H); 8.55 (d, 1H, J = 6.4 Hz); 8.10 (bs, 1H) 7.47 (d, 1H, J = 6.4 Hz); 7.15 (s, 1H); 7.02 (s, 1H); 5.6 (s, 1H); 5.1 (t, 1H, J = 6.4 Hz) 4.53 (bd, 2H); 3.49 (dd, 1H, J = 6.4; 10.4 Hz); 3.41 (dd, 1H, J = 6.4; 10.4 Hz) 1.48 (s, 3H); 1.27 (t, 3H, J = 7.2 Hz).

For the two enantiomers, Berger SFC, 230 nm UV detection, stationary phase Chiralpak AD-H (250 mm × 4.6) 5 μm, mobile phase 60/40% CO 2 /(isopropanol+0.5% isopropylamine), 2.4 ml / min The optical purity was analyzed using the Chiral SFC method at 100 bar.
R-form (tr = 8.37 min, enantiomeric purity = 99.2%).
Form S (tr = 7.29 min, enantiomeric purity = 98.5%).

Example 4: (Compound No. 4)
2-Amino-1-ethyl-7- (3-hydroxy-3-pyridin-2-ylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine-4 -On Intermediates described in 1.6 (2-amino-7-chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [ 1,8] naphthyridin-4-one) and similarly coupled with (±) -2-pyridin-2-ylbut-3-in-2-ol according to the detailed procedure outlined in Example 1. To give the title compound.
_{MH + = 401.21 (C 22 H} 20 N 6 O 2, Mr = 400.44).
Rt (analytical HPLC): 4.49 min.

Example 5: (Compound No. 5)
2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- (4-methyl-1H-imidazol-2-yl) ) -1H- [1,8] naphthyridin-4-one 5.1: 4-Methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2-carbaldehyde 4 (5)-in DMF 73 ml Example 1 starting from 4 g (36.3 mmol) of methyl-1H-imidazole-2-carbaldehyde, 1.5 g (38 mmol) of sodium hydride and 6.7 g (40 mmol) of 2- (trimethylsilanyl) ethoxymethyl chloride Using the same procedure as in step 1.3, 8.7 g of the title compound was obtained as a brown oil (quantitative yield).
_{MH + = 241 (C 11 H} 20 N 2 O 2 Si, 240.377).

5.2: [4-Methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] acetonitrile 4-methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole- Example 1 starting from a solution of 8.7 g (32.7 mmol) of 2-carbaldehyde, 6.7 g (34.3 mmol) of TOSMIC and 7.3 g (65 mmol) of potassium tert-butylate in anhydrous DME (54 ml). Using the same procedure as described in 1.4, 6.6 g of a yellow oily compound was obtained as a 70/30 mixture of τ and π regioisomers.
Yield = 80%.
_{MH + = 252 (C 12 H} 21 N 3 OSi, 251.404).
Tr = 6.38 minutes and 6.55 minutes.

5.3: 2-Amino-7-chloro-1-ethyl-3- [4-methyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8 ] Naphthyridin-4-one 6.3 g (25 mmol) of the compound obtained after step 6.2, 5 g (25 mmol) of the compound obtained after step 1.2, and 7.2 g (62 mmol) of potassium tert-butyrate anhydrous Beige as an 80/20 mixture of two isomers of τ and π, starting from a THF (83 ml) solution and using the same procedure as described in Example 1, steps (1.5-1.6) 4 g of a colored powder product was obtained and used as a mixture in the next step.
Yield = 38%.
Melting point = 120 ° C.
_{MH + = 435 (C 20 H} 28 ClN 5 O 2 Si, 434,013).
Tr = 10.5 minutes and 10.6 minutes.
1H NMR of both isomers (500 MHz, DMSO-d6) δ ppm 8.45 (d, J = 8.07 Hz, 2H) 7.70 (bs, 2H) 7.56 (bs, 2H) 7.43 (d, J = 8.07 Hz, 1H) 7.42 (d, J = 8.07 Hz, 1H) 6.99 (m, 1H) 6.84 (m, 1H) 5.18 (s) , 2H) 5.17 (s, 2H) 4.43 (q, J = 6.85 Hz, 4H) 3.19 (m, 2H) 3.12 (m, 2H) 2.25 (d, J = 0 .98 Hz, 3H) 2.16 (d, J = 0.98 Hz, 3H) 1.24-1.29 (m, 6H) 0.57-0.64 (m, 4H) -0.22 (s, 9H) -0.22 (s, 9H).

5.4: 2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- [4-methyl-1- ( 2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one Compound 0 obtained after step 5.3 in an argon-substituted microwave reaction flask. 0.5 g (1.15 mmol), (R) -1-methoxy-2-methylbut-3-in-2-ol 0.26 g (2.3 mmol), and bis (triphenylphosphine) palladium (II) dichloride 40 mg (0.06 mmol), copper (I) iodide 22 mg (0.12 mmol), DMF (degassed) 3 ml, and triethylamine (degassed) 3 ml were heated to 80 ° C. for 3 hours. The solvent was evaporated and the solid was dissolved in ethyl acetate and washed sequentially with saturated aqueous NaHCO ₃ and HCl (1N). The organic phase was then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (DCM / THF 95/5: MeOH (1% NH ₄ OH) 0% → 10%) to give 0.19 g of the title compound.
Yield: 32%.
_{MH + = 512 (C 26 H} 37 N 5 O 4 Si, 511.695).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 7.91 Hz, 2H) 7.69 (br.s., 2H) 7.55 (br.s., 2H) 7.41 ( d, J = 7.79 Hz, 2H) 6.99 (s, 1H) 6.84 (s, 1H) 5.81 (s, 2H) 5.18 (s, 4H) 4.40-4.58 ( m, 4H) 3.47 (d, J = 9.54 Hz, 2H) 3.37-3.43 (m, 8H) 3.19 (t, J = 8.02 Hz, 2H) 3.12 (t, J = 8.08 Hz, 2H) 2.26 (s, 3H) 2.17 (s, 3H) 1.47 (s, 6H) 1.26 (t, J = 6.57 Hz, 6H) 0.54- 0.67 (m, 4H)-0.23 (s, 18H).

5.5: 2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-in-1-yl] -3- (4-methyl-1H-imidazole) 2-yl) -1H- [1,8] naphthyridin-4-one 0.18 g (0.36 mmol) of the compound obtained after step 5.4 was dissolved in TFA 1.7 ml and DCM 1.7 ml at 0 ° C. The solution was maintained at 3-5 ° C. overnight. The solution was neutralized by adding excess aqueous NaHCO ₃ solution. The mixture was then extracted 3 times with ethyl acetate. The organic phases were combined and dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by crystallization in DCM to give 62 mg (46% yield) of the unprotected title compound.
_{MH + = 382 (C 20 H} 23 N 5 O 3, 381.434).
1H NMR (DMSO-d6,500 MHz): (two phase isomers on imidazole were detected in 60/40 ratio) δ = 12.9-12.8 (2s, 1H) 11.6 (brs, 1H) 8.52 (d, J = 7.9 Hz, 1H) 8.0 (brs, 1H) 7.42 (d, J = 7.9 Hz, 1H) 6.84-6.70 (2s, 1H) 5.8 (s, 1H) 4.56 (m, 2H) 3.46 (d, J = 9.5 Hz, 1H) 3.3 (s, 3H) 3.4 (d, J = 9.5 Hz, 1H) 2.28-2.2 (2s 3H) 1.47 (s, 3H) 1.28 (t, J = 6.6 Hz, 3H).

Example 6: (Compound No. 6)
2-Amino-1-cyclopropylmethyl-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one 6.1 : 6-chloro-2- (cyclopropylmethylamino) nicotinic acid In a sealed tube, add 3 g (42 mmol) of cyclopropylmethylamine to a solution of 3 g (14 mmol) of 2,6-dichloronicotinic acid in tert-butanol (14 ml). The tube was sealed and heated in a Biotage Initiator microwave to 170 ° C. for 30 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane (100 ml) and washed with 10% aqueous acetic acid (12 ml). The organic phase was dried over Na ₂ SO ₄ , filtered, concentrated and dried under reduced pressure. 3.4 g of product was obtained as an orange oil.
Quantitative yield.
MH + = 227.
Tr = 4.54 minutes.

6.2: 6-chloro-2- (cyclopropylmethylamino) nicotinoyl fluoride A solution obtained by dissolving 0.334 g (1.4 mmol) of the compound obtained after Step 7.1 in 4 ml of dichloromethane, and cyanuric fluoride 0 Starting from .38 g (2.8 mmol) and 0.28 g (2.8 mmol) of triethylamine, using the same procedure as described in step 1.2 of Example 1, the product obtained as a green oil The product was used in the next step without purification.

6.3: 2-amino-7-chloro-1- (cyclopropylmethyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8 ] Naphthyridin-4-one A solution of the crude compound obtained after step 6.2, 0.32 g (1.4 mmol) of the compound obtained after step 1.3 in 5 ml of anhydrous THF, and potassium tert-butylate 0.8. Starting from 4 g (0.35 mmol), using the same procedure as described in Example 1 steps (1.5-1.6), 0.56 g of product was obtained as a brown powder.
Yield = 90%.
Melting point = 70 ° C.
_{MH + = 447 (C 21 H} 28 ClN 5 O 2 Si).
Tr = 6.68 minutes.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (d, J = 8.05 Hz, 1H) 7.67 (br.s, 2H) 7.43 (d, J = 8.05 Hz, 1H) 35 (d, J = 1.37 Hz, 1H) 7.12 (d, J = 1.19 Hz, 1H) 5.27 (s, 2H) 4.38 (d, J = 7.04 Hz, 2H) 19-3.25 (m, 2H) 1.21-1.32 (m, 1H) 0.59-0.68 (m, 2H) 0.45-0.57 (m, 4H) -0.21 (S, 9H).

6.4: 2-amino-1- (cyclopropylmethyl) -7- (3-hydroxypent-1-ynyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazole-2- Yl] -1H- [1,8] naphthyridin-4-one 0.5 g (1.2 mmol) of the compound obtained after step 6.3, and 0.22 g (2.5 mmol) of penta-4-yne-3-ol. ), Bis (triphenylphosphine) palladium (II) dichloride 43 mg (0.06 mmol), copper (I) iodide 23 mg (0.12 mmol), DMF (degassed) 3 ml, triethylamine (degassed) 3 ml Using the same procedure as described in step 5.4 of Example 5, starting from, 0.19 g of the title compound was obtained.
Yield = 30%.
_{MH + = 494 (C 26 H} 35 N 5 O 3 Si, 493.68).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J = 7.87 Hz, 1H) 7.65 (br.s, 2H) 7.42 (d, J = 7.87 Hz, 1H) 33 (s, 1H) 7.10 (s, 1H) 5.63 (d, J = 5.58 Hz, 1H) 5.28 (s, 2H) 4.38-4.52 (m, 3H) 17-3.25 (m, 2H) 1.67-1.76 (m, 2H) 1.22-1.31 (m, 1H) 1.01 (t, J = 7.36 Hz, 3H) 59-0.66 (m, 2H) 0.44-0.57 (m, 4H) -0.24-0.20 (m, 9H).

6.5: 2-amino-1-cyclopropylmethyl-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine-4- ON Starting from a solution of 0.18 g (0.36 mmol) of the compound obtained after step 7.4 in 1.7 ml of TFA and 1.7 ml of DCM, the same procedure as described in step 5.5 of example 5 is used. Used to give 19 mg of the title compound.
Yield = 15%.
Melting point = 252 ° C.
_{MH + = 364 (C 20 H} 21 N 5 O 2, 363.419).
1H NMR (400 MHz, DMSO-d6) δ ppm 13.15 (br s, 1 H) 11.5 (br s, 1 H) 8.56 (d, J = 7.9 Hz, 1 H) 8.0 (br. S, 1H) 7.45 (d, J = 7.9 Hz, 1H) 7.15 (m, 2H) 5.62 (brs, 1H) 4.62 (m, 2H + 1H) 1.75 (m, 2H) 1 .34 (m, 1H) 1.05 (t, J = 7.36 Hz, 3H) 0.5 (m, 2H) 0.48- (m, 2H).

Example 7: (Compound No. 7)
2-Amino-1-ethyl-7-((R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H-quinoline-4- 7.1: 2-Fluoro-4-iodobenzoic acid To an aqueous suspension of 2-fluoro-4-iodotoluene 5 g (21.18 mmol) and pyridine 25.13 g (317.77 mmol), potassium permanganate 13. 39 g (84.74 mmol) was added. The mixture was heated and stirred at 70 ° C. for 18 hours. Since the reaction was not complete, 3.34 g (21.18 mmol) of potassium permanganate was added to the reaction mixture at room temperature and the mixture was stirred at 70 ° C. for a further 6 hours. The reaction mixture was then filtered through a pad of celite and washed with water and ethyl acetate. After decanting, 6N aqueous HCl was added to acidify the aqueous phase to pH = 1. The white solid was first filtered and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and dried over MgSO ₄ and the solvent was evaporated under reduced pressure. The filtered white solid and the solid extracted with ethyl acetate were combined to obtain 4.1 g.
Yield = 73%.
_{MH + = 266.9 (C 7 H} 4 FIO 2).
1H NMR (DMSO-d6, 400 MHz): δ 13.49 (broad signal, 1H); 7.88 (d, 1H); 7.78 (d, 1H); 7.65 (d, 1H).

7.2: 2-ethylamino-4-iodobenzoic acid 3.5 g (13.16 mmol) of 2-fluoro-4-iodobenzoic acid was mixed with 16.11 ml of a solution of ethylamine (70% aqueous solution) in a sealed tube. . The reaction vessel was heated and heated at 125 ° C. for 24 hours. Nitrogen was bubbled through the reaction mixture to remove excess ethylamine. The reaction mixture was then poured into ice water and acetic acid was added to acidify the mixture from pH = 3-4. The resulting white solid was then filtered off, washed with water and dried to give 2.2 g (7.55 mmol).
Yield = 58%.
_{MH + = 291.8 (C 9 H} 10 INO 2).
1H NMR (DMSO-d6, 400 MHz): δ 12.5 (brs, 1H); 7.55 (d, 1H); 7.11 (s, 1H); 6.9 (d, 1H).

7.3: 1-ethyl-7-iodo-1H-benzo [d] [1,3] oxazine-2,4-dione 2-ethylamino-4-iodobenzoic acid 2.2 g (7.55 mmol) was added to dioxane. To a solution dissolved in 30 ml, 0.785 g (2.65 mmol) of triphosgene was added at room temperature. The reaction mixture was then heated and stirred at 110 ° C. for 2 hours. The solution was evaporated to dryness and 20 ml of toluene was added twice and then re-evaporated twice to give 2.39 g (7.5 mmol) of solid.
Yield = 100%.
_{MH + = 317.7 (C 10 H} 8 INO 3).
1H NMR (DMSO-d6, 400 MHz): δ 7.87 (s, 1H); 7.68 (s, 2H); 4.04 (m, 2H); 1.19 (t, 3H).

7.4: 2-Amino-1-ethyl-7-iodo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 1-ethyl-7-iodo-1H-benzo [d] [1,3] To a solution obtained by dissolving 2 g (6.31 mmol) of oxazine-2,4-dione in 25 mL of DMF, 0.32 g (6.31 mmol) of malononitrile and 1.45 g (14.35 mmol) of triethylamine were added. The solution was stirred at 120 ° C. for 2 hours, 0.73 g (7.17 mmol) of triethylamine was added, and further stirred at 110 ° C. for 1 hour. DMF was then evaporated under reduced pressure and the residue was dissolved in a mixture of water and dichloromethane. This mixture was filtered to give 0.55 g (1.62 mmol) of the first fraction of the expected compound.
Yield = 26%.
_{MH + = 339.7 (C 10 H} 8 INO 3).
1H NMR (DMSO-d6, 400 MHz): δ 7.9 (s, 1H); 7.80 (d, 1H); 7.7 (m, 2H); 4.21 (m, 2H); 1.20 ( t, 3H).

7.5: 2-Amino-N- (2,2-diethoxyethyl) -1-ethyl-7-iodo-4-oxo-1,4-dihydroquinoline-3-carboxamidine 2-amino-1-ethyl- 7-Iodo-4-oxo-1,4-dihydroquinoline-3-carbonitrile 0.48. To a solution of g (1.43 mmol) dissolved in 20 ml of DME, 0.38 g (2.86 mmol) of aminoacetaldehyde diethyl acetal and 0.155 g (1.57 mmol) of CuCl were added. The solution was stirred and irradiated with microwaves at 100 ° C. for 0.5 hours.

The solution was then filtered off and evaporated to dryness. The crude product was then purified by column chromatography (DCM / MeOH: 9/1) to give 0.57 g (1.2 mmol) of a solid.
Yield = 78%.
_{MH + = 473 (C 18 H} 25 IN 4 O 3).

7.6: 2-amino-1-ethyl-3- (1H-imidazol-2-yl) -7-iodo-1H-quinolin-4-one 2-amino-N- (2,2-diethoxyethyl) To a suspension of 0.13 g (0.28 mmol) of -1-ethyl-7-iodo-4-oxo-1,4-dihydroquinoline-3-carboxamidine, 0.37 ml of 12N HCl solution was added at 0 ° C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with 0.55 ml of water and basified by addition of 0.32 ml of 1N NaOH solution and 0.134 ml of NH ₄ OH solution. The mixture was then filtered and the resulting solid was washed with water, acetonitrile and pentane to give 0.08 g (0.21 mmol) of a brown solid.
Yield = 76%.
_{MH + = 381 (C 14 H} 13 IN 4 O).

7.7: 2-amino-1-ethyl-7-((R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- Quinolin-4-one 2-amino-1-ethyl-3- (1H-imidazol-2-yl) -7-iodo-1H-quinolin-4-one 0.43 mg (1.15 mmol) and (R)- 3-hydroxy-4-methoxy-3-methylbut-1-yne 0.262 (23 mmol) and 0.397 g (3.45 mmol) were mixed in 15 ml of DMF. This solution was bubbled with argon for 10 minutes. After the addition of 0.126 mg (0.17 mmol) of 1,1′-bis (diphenylphosphino) ferrocenepalladium dichloride and 0.033 mg (0.17 mmol) of copper iodide, the reaction mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was then evaporated to dryness and the residue was poured into a mixture of DCM and water. The black insoluble solid was filtered off (100 mg). The aqueous phase was extracted 3 times with dichloromethane. The organic phases were combined and dried over MgSO ₄ and the solvent was evaporated under reduced pressure. Next, the residue was purified by column chromatography (DCM / MeOH / NH4OH aqueous solution: 9/1 / 0.1) to obtain 0.80 g (1.2 mmol) of a yellow solid. This solid was recrystallized in dichloromethane to give 0.02 g of a beige solid.
Yield = 4.5%.
_{MH + = 367 (C 20 H} 22 N 4 O 3, 366.419).
1H NMR (DMSO-d6, 400 MHz): δ 13.19 (s, 1H); 8.27 (d, 1H); 7.61 (s, 1H); 7.31 (d, 1H); 7.13 ( 7.02 (s, 1H); 6.94 (broad signal, 2H); 4.36-4.28 (broad signal, 2H); 3.45-3.25 (broad signal, water) Peak + 4H); 1.46 (s, 3H); 1.31 (t, 3H).

Example 8: (Compound No. 8)
2-Amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one 8.1: 2 -Amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8 ] Naphthyridin-4-one 2-Amino-7-chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [ 1,8] naphthyridin-4-one 0.3 g (0.71 mmol), 3-chloro-4-hydroxyphenylboronic acid 0.185 g (1.07 mmol), tris (dibenzylideneacetone) dipara Um (0) 0.098 g (0.11 mmol), tricyclohexylphosphine 0.030 mg (0.0.11 mmol), tripotassium phosphate 0.303 g, dioxane / water (50/50) (degassing) 8 mL was heated and stirred at 85 ° C. for 8 hours. The solvent was evaporated and the residue was purified by column chromatography (DCM / MeOH: 9/1) to give 0.4 g of a brown solid. This solid was used in the next step without further purification.

8.2: 2-amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one Of 2-amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1 , 8] naphthyridin-4-one 400 mg (0.59 mmol) was dissolved in 20 ml DCM. At 0 ° C., 3.39 g of TFA was added and the mixture was stirred at room temperature for 24 hours. The solution was neutralized by adding excess aqueous NaHCO ₃ solution. The mixture was then extracted 3 times with DCM. The organic phases were combined and dried over MgSO ₄ and the solvent was evaporated under reduced pressure. The crude product thus obtained was purified on silica gel (DCM: MeOH: NH ₄ OH = 4: 10.1) to give 0.035 g of the unprotected title compound.
Yield of 2 steps = 13%.
_{MH + = 382 (C 19 H} 16 ClN 5 O 2, 381.821).
1H NMR (DMSO-d6, 400 MHz): δ 13.19 (s, 1H); 8.55 (d, 1H); 8.2 (s, 1H); 8.04 (dd, 1H); 7.9 ( 7.15 (s, 1H); 7.09 (d, 1H); 7.3 (s, 1H); 4.72-4.66 (m, 2H); 1.37 (t , 3H).

Example 9: (Compound No. 9)
2-Amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine -4-one 9.1: 2-amino-1-ethyl-7-chloro-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one 2-amino-7- Chloro-1-ethyl-3- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one (1.0 g, 2.38 mmol) ) Was dissolved in 30 mL of dichloromethane. 30 mL of trifluoroacetic acid was added and the reaction mixture was stirred at room temperature for 3 hours until analytical HPLC judged that the starting material was completely consumed. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The solution was washed with saturated aqueous sodium bicarbonate. The formed precipitate was collected by filtration and dried under reduced pressure at 40 ° C. overnight to obtain 574 mg of a beige powder.
Yield = 83%.
1H NMR (DMSO-d6, 600 MHz): δ (ppm) 13.09 (s, 1H); 8.57 (d, 1H); 7.47 (d, 1H); 7.15 (s, 1H); 7.03 (s, 1H); 4.51 (bq, 2H); 1.29 (t, 3H).

9.2: 2-Amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1 , 8] naphthyridin-4-one copper (I) iodide (23.7 mg, 0.12 mmol), N-ethylmorpholine (130 μL, 1.04 mmol), 2- (2-fluorophenyl) but-3- In-2-ol (76 μL, 0.52 mmol) was added to 2.5 mL of DMF. The mixture was degassed with argon. [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) chloride and dichloromethane 1: 1 adduct (5.6 mg, 0.01 mmol) and intermediate 20.1 (100 mg, 0.35 mmol) Was added. The mixture was stirred at 80 ° C. for 2 hours under an argon atmosphere until no starting material remained by LCMS. Ethyl acetate was added. The organic layer was washed successively with water, 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was then purified by column chromatography (DCM / MeOH / NH ₄ OH aqueous solution: 100/0/0 → 95/5 / 0.5) to obtain 30 mg of an off-white powder.
Yield = 21%.
MH + = 418.
Rt = 0.57 min _{(C 23 H 20 FN 5 O} 2, 417.442).
1H NMR (DMSO-d6, 600 MHz): δ 13.10 (bs, 1H); 8.54 (d, 1H); 7.72 (dt, 1H); 7.44 (d, 1H); 7.38 ( m, 1H); 7.25-7.19 (m, 2H); 7.13 (d, 1H); 7.02 (d, 1H); 6.62 (s, 1H); 4.54 (bq) , 2H); 1.84 (s, 3H); 1.27 (t, 3H).

Example 10: (Compound No. 12)
2-Amino-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1- (2-methoxyethyl) -1H- [1,8] naphthyridin-4-one Starting from step 1 with 2-methoxyethanamine instead of cyclopropylmethylamine and following a procedure similar to that described in steps 1 and 2 of Example 6, 2- (2-fluorophenyl) buta- Starting from penta-1-in-3-ol instead of 3-in-2-ol, following the same procedure as step 2 of Example 20, 15 mg of product was obtained as a powder.
MH + = 368.
Rt = 0.46 min _{(C 19 H 21 N 5 O} 3 367,407).

Example 11: (Compound No. 19)
2-Amino-1-ethyl-3- (1H-imidazol-2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl) -1H- [1 , 8] naphthyridin-4-one 11.1: 2-amino-1-ethyl-7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl) -3- [1 -(2-Trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one 2-amino-7-chloro-1-ethyl-3- [1- ( 2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] -1H- [1,8] naphthyridin-4-one 0.4 g (0.95 mmol) and 1,1,1-trifluoro-2 -Phenylbut-3-yne-2- 0.4 g (1.9 mmol), bis (triphenylphosphine) palladium (II) dichloride 33 mg (0.05 mmol), copper (I) iodide 18 mg (0.1 mmol), DMF (degassed) 3 ml And using the same procedure as described in step 5.4 of Example 5, starting from 3 ml of triethylamine (degassed) gave 0.15 g of the title compound.
Yield = 30%.
_{MH + = 584 (C 29 H} 32 N 5 O 3 Si).
1H NMR (250 MHz, DMSO-d6) δ ppm 8.52 (d, J = 7.91 Hz, 1H) 8.21 (s, 1H) 7.76-7.84 (m, 2H) 7.72 (br. s, 2H) 7.64 (d, J = 7.91 Hz, 1H) 7.46-7.57 (m, 3H) 7.33 (d, J = 1.34 Hz, 1H) 7.10 (d, J = 1.34 Hz, 1H) 5.28 (s, 2H) 4.44-4.57 (m, 2H) 3.16-3.27 (m, 2H) 1.28 (t, J = 6. 91 Hz, 3H) 0.57-0.69 (m, 2H) -0.22 (s, 9H).

11.2: 2-amino-1-ethyl-3- (1H-imidazol-2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl)- 1H- [1,8] naphthyridin-4-one Starting with 0.145 g (0.25 mmol) of the compound obtained after step 21.1 in 1.2 ml TFA and 1.2 ml DCM, step 5. Using the same procedure described in 5, 5 mg of the title compound was obtained.
Yield = 86%.
Melting point = 260 ° C.
_{MH + = 454 (C 23 H} 18 F 3 N 5 O 2).
Rt = 7.29 min.
1H NMR (400 MHz, DMSO-d6), δ ppm 13.12 (br.s., 1H) 11.58 (br.s., 1H) 8.63 (d, J = 7.87 Hz, 1H) 8.21 (S, 1H) 8.19 (br. S, 1H) 7.77-7.82 (m, 2H) 7.66 (d, J = 7.87 Hz, 1H) 7.46-7.55 (m , 3H) 7.14 (br.s., 2H) 4.57 (q, J = 6.59 Hz, 2H) 1.30 (t, J = 7.00 Hz, 3H).

  Compounds 10 and 11 were prepared by procedures similar to those described in Example 6.

  Compounds 13, 14, 15, 16, 17, 18, 20, 21, 25 were prepared by procedures similar to those described in Example 10.

  Compounds 22, 23 and 24 were prepared by a procedure similar to that described in Example 11.

  Compound 29 was prepared by a procedure similar to that described in Example 1.

Apparatus used in Examples 5 and 6 Microwave apparatus: Biotage, initiator

Analytical Method LC / UV / MS Retention Time (Rt) Detection LC / UV / MS analytical method used to analyze compounds 1, 2, 3 and 4 (Rt):
Column: Merk Chromolis performance RP18e, 100 × 4.6 mm, 3.5 μm
Solvent A: H ₂ O / TFA (99.9 / 0.1)
Solvent B: ACN / TFA (99.9 / 0.1)
Flow rate: 2 ml / min Gradient (A / B): 98/2 (0 min) → 0/100 (8 min) → 98/2 (10 min)
Detection: 254.16 nm.

LC / UV / MS analytical method used to analyze compounds 9, 12, 13, 14, 17, 18 and 20 (Rt):
UPLC SQD electrospray ionization, positive ion mode (30V)
Column: Ascentis Express 50 × 2.1 mm 2.7 μm, T = 55 ° C.
Solvent A: H ₂ O + 0.02% TFA
Solvent B: CH ₃ CN + 0.014% TFA
Flow rate: 1 mL / min gradient (A / B v / v): 98/2 (t = 0 min), 2/98 (t = 1 min), 2/98 (t = 1.3 min), 98/2 (T = 1.33 minutes), next injection (t = 1.5 minutes)
Detection: 220 nm.

Analytical methods used to analyze compounds 5, 6, 10, 11, 19, 22, 23 and 24:
HPLC system: 1100 series mass spectrometer MSD SL (Agilent)
Software: Agilent product Chemstation version 01.03
Ionization mode: Electrospray positive ion mode ESI +
Mass range: 90-1500uma
Column: Symmetry C18 3.5 μm (2.1 × 50 mm) (Waters) T = 25 ° C., pH: 3
Eluent A: H ₂ O + 0.005% TFA
B: CH ₃ CN + 0.005% TFA
Flow rate: 0.4 ml / min Gradient: 0 → 10 minutes 0 → 100% B and 10 → 15 minutes 100 B%
Detection: 220 nm.

LC / UV / MS analysis method used for compounds 7, 8, 15, 16, 21, 25, 26 (Rt):
UPLC LCT electrospray ionization, positive ion mode (15V, 30V)
Software: Masslyx V4.1
Column: Acquity UPLC BEH C1850 × 2.1 mm 2.7 μm, T = 40 ° C.
Solvent A: H ₂ O + 0.05% TFA
Solvent B: CH ₃ CN + 0.035% TFA
Flow rate: 1 mL / min Gradient (A / Bv / v): 98/2 (t = 0 min), 0/100 (t = 1.6 min), 0/100 (t = 2.1 min), 98 / 2 (t = 2.5 minutes), next injection (t = 3 minutes)
Detection: 220 nm.

NMR
Using the DMSO-d5 peak as an internal standard, a 1H NMR spectrum was obtained using an NMR spectrometer Bruker 250, 300, 400 or 600 MHz in DMSO-d6. The chemical shift δ is expressed in parts per million (ppm).

  The observed signal is expressed as: s = single line; d = double line; t = triple line; q = quadruple line; m = multiple line or wide single line; br = broad; H = proton.

Melting points Melting points below 260 ° C were measured with a Kofler bench, and melting points above 260 ° C were measured using a Buchi B-545 instrument.

Optical rotation power was measured with a polarimeter Perkin-Elmer, a polarimeter with a supply current of 55 μA.

  The compounds of the present invention were subjected to a pharmacological assay to determine their inhibitory effect on autophosphorylation of VEGFR-3 and to evaluate its ex vivo activity as described in the assay below.

Effect of compounds on VEGFR-3 autophosphorylation in HEK cells The effect of compounds on inhibition of VEGFR-3 autophosphorylation after overexpression of VEGFR-3 in HEK cells was quantified by ELISA. HEK293T cells were maintained in MEM supplemented with 10% fetal calf serum (FCS) and glutamine. The day before transfection, 104 cells were seeded per well in a 48-well plate, and transfection was performed using Fugene-6 (Roche, Basel). To Fugene-6 (18 μL), 282 μl of optimem was added and preincubated for 5 minutes. Next, 3 μg of DNA corresponding to VFGR-3-Flag was added and allowed to stand at room temperature for 10 minutes, and then 200 μl was distributed on HEK cells. After 24 hours, the medium was discarded and replaced with fresh serum-free medium, and each compound at various concentrations (3 to 1000 nM) was added and incubated for 1 hour. Orthovanadate (0.4 mM) was added and further incubated for 30 minutes, and then the cells were washed with cold PBS supplemented with orthovanadate and then lysed with 300 μl of RIPA buffer. The lysate was then centrifuged at 10,000g for 10 minutes. The supernatant (75 μl) was distributed to two 96-well plates pre-coated with anti-Flag and left at room temperature for 1 hour. After washing 3 times with TBS buffer supplemented with 0.5% tween 20, anti-phosphotyrosine conjugated to HRP was added and incubated at room temperature for 1 hour. Thereafter, the wells were washed three times with TBS buffer supplemented with tween 20 (0.5%) and MgCl ₂ (2 mM). The reaction was stopped by adding 50 μl of H ₂ SO ₄ (2N), and the signals at 485 and 530 were read with Envision.

  Ratkovsky and Reedy (Ratkovsky DA., Reedy TJ. Choosing near-linear parameters in the four parameters logistic ss. Concentration response curves were analyzed with the software Biost @ t-SPEED v2.0.

The compounds of the present invention have inhibitory activity against autophosphorylation of VEGFR-3 and show IC ₅₀ values of less than 1 μM, especially 1 to 500 nM, more particularly 1 to 100 nM, in autophosphorylation in HEK cells.

As an example, the IC ₅₀ values for the compounds in Table 1 are shown in Table 2 below.

  Inhibitors of VEGFR-3 tyrosine kinase according to the present invention show good ex vivo activity when using an assay that measures inhibition of autophosphorylation of VEGFR3 and are better than one of the prior art inhibitors.

Ex vivo assay Protocol for administration of formulation to mice:
Prepare the formulation by adding 0.5% Tween 80 and 0.6% methylcellulose to a sufficient final volume in the mortar. Suspensions are administered by gavage (10 ml / kg) to 8-15 week old male Balb / c mice. Three or six hours after a single oral administration of 30 mg / kg, the animals were anesthetized with pentobarbital, and a blood sample (400 μL) was collected from the vena cava and transferred to a glass tube containing lithium heparin. After centrifugation (1500-000 g for 10 minutes), plasma samples were frozen at a temperature around −20 ° C. until analysis.

  The HEK cell autophosphorylation assay was used to detect the ex vivo activity of the formulation in plasma. For this purpose, transfected cells were incubated with plasma (10%) instead of compound. Results are expressed as percent inhibition of VEGFR-3 autophosphorylation compared to untreated cells (maximum autophosphorylation) and untransfected cells (background).

  The ex vivo activities of the compounds of the present invention are summarized in Table 3 below. Results are expressed as the percentage inhibition of VEGFR-3 autophosphorylation in HEK cells in the presence of plasma samples taken (at a time) after oral (po) administration of the compound. In order to evaluate this enhanced activity of the compounds of the present invention, Table 3 compares to the compounds of the prior art (WO2009 / 007535) that made the same measurements.

  As described above, since the compound of the present invention has an inhibitory activity against autophosphorylation of VEGFR-3, it is apparent that it can be used for the production of a pharmaceutical, particularly a pharmaceutical that inhibits VEGFR-3.

  Compound exposure, particularly increased bioavailability, is one condition that improves ex vivo inhibition of VEGFR3 autophosphorylation by the compounds of the present invention.

  The VEGFR-3 tyrosine kinase inhibitors of the present invention exhibit good bioavailability and are better than one of the prior art inhibitors.

  Bioavailability means the rate and rate at which an active moiety (drug or metabolite) enters the systemic circulation and reaches the site of action.

  The bioavailability of a drug is not determined by the physicochemical properties of the drug that determine its absorbability, but mainly by the nature of the dosage form (which also depends on its design and process). Because the difference in bioavailability between formulations of a given drug is considered clinically important, it is essential to know whether the drug formulations are equivalent.

  Bioavailability is used to represent the percentage of drug that reaches the systemic circulation unchanged with respect to dose, and such percentage is one of the major pharmacokinetic properties of the drug. By definition, when a drug is administered intravenously, its bioavailability is 100%. On the other hand, if the drug is administered by other routes (eg, oral), its bioavailability is reduced (due to incomplete absorption and first-pass metabolism) and may vary between patients (due to interindividual variation) . Bioavailability is one of the essential tools in pharmacokinetics because it needs to be taken into account when calculating doses for non-intravenous routes of administration.

  Thus, according to another aspect, the subject of the present invention is a compound of formula (I), including a compound of formula (I), or an addition salt of said compound and a pharmaceutically acceptable acid or base, and mixtures thereof. A pharmaceutical containing an enantiomer or diastereomer.

  Another aspect of the present invention includes a combination of at least one compound of the present invention and at least one therapeutic agent.

Specifically, the compounds of the present invention may be used alone or
An alkylating agent,
-Intercalating agents,
-An anti-microtubule agent,
An antimitotic agent,
An antimetabolite,
An antiproliferative agent,
-Antibiotics,
An immunomodulator,
-Anti-inflammatory agents,
A kinase inhibitor,
-Anti-angiogenic agents,
-A vascular therapeutic agent,
-It may be used as a mixture with at least one therapeutic agent which can be selected from female and male hormones.

  It is also possible to use the compounds of the present invention in combination with radiation therapy.

  Combinations of the compounds of the present invention with the above therapeutic agents and / or radiation are also subjects of the present invention.

  The therapeutic agent and / or radiation can be administered simultaneously, separately or sequentially. The treatment is adjusted by the physician according to the patient being treated.

These medicines are especially
-Cancer and its metastases (eg glioblastoma, multiple myeloma, myelodysplastic syndrome, Kaposi's sarcoma, cutaneous hemangiosarcoma, solid tumor, lymphoma, melanoma, breast cancer, colorectal cancer, lung cancer including non-small cell carcinoma) Treatment of pancreatic cancer, prostate cancer, kidney cancer, head and neck cancer, liver cancer, ovarian cancer, airway and breast cancer, other tumors that express VEGFR-3 or involve angiogenesis or lymphangiogenesis processes) and / or Or prevention,
Non-cancerous proliferative diseases and pathological angiogenesis related to VEGFR-3 (eg arthropathy, restenosis, psoriasis, hemangiomas, lymphangioma, glaucoma, glomerulonephritis, diabetic nephropathy, nephrosclerosis, Treatment and / or prevention of thrombotic microangiopathies syndrome, cirrhosis, atherosclerosis, organ transplant rejection, ocular diseases with angiogenesis or lymphangiogenesis processes (eg diabetic retinopathy and macular degeneration),
-Or treatment and prevention of (chronic or non-chronic) inflammation, microbial infections and autoimmune diseases (eg rheumatoid arthritis),
-Or as a therapeutic agent in the treatment of rare diseases such as lymphangioleiomyomatosis and Gorham's disease .

  According to another aspect, the present invention relates to a pharmaceutical composition comprising a compound of the present invention as an active ingredient. These pharmaceutical compositions comprise an effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of said compound, and at least one pharmaceutically acceptable dose. Contains a dosage form.

  The excipient is selected from conventional excipients known to those skilled in the art depending on the desired dosage form and administration method.

  In the pharmaceutical composition of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, topical, intratracheal, intranasal, transdermal or rectal administration, the above formula (I) or a possible salt or solvent thereof The active ingredient of a hydrate or hydrate can be administered in a unit dosage form as a mixture with a conventional pharmaceutical excipient to animals or humans for the purpose of treating or preventing the above disorders or diseases.

  Suitable unit dosage forms include oral dosage forms such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms, Examples include inhaled dosage forms, external, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms, and implants. For topical use, the compounds of the invention can be used in creams, gels, ointments or lotions.

By way of example, a unit dosage form of a compound of the invention in tablet form may contain the following ingredients:
50.0 mg of the compound of the present invention
Mannitol 223.75mg
Croscarmellose sodium 6.0mg
Corn starch 15.0mg
Hydroxypropyl methylcellulose 2.25mg
Magnesium stearate 3.0 mg.

  According to another aspect, the present invention also relates to a method for treating the above diseases comprising the step of administering to a patient an effective dose of a compound of the present invention or a pharmaceutically acceptable salt thereof.

Claims (23)

Formula (I):

[Where:
-W represents a nitrogen atom or a CH group;
-Y is optionally substituted with R ₇ representing a 1 or more halogen atom, C ₂ -C ₃ alkynylene group, a 1,4-phenylene group;
-Z represents a bond or a CR ₁ R ₂ group;
-R ₁ and R ₂ are each independently a hydrogen atom, C ₁ -C ₆ alkyl group, trifluoromethyl group, (CH ₂ ) _n OR ₆ group, C ₃ -C ₇ cycloalkyl group, heteroaryl group Or represents a group selected from aryl groups, wherein the heteroaryl group or aryl group is optionally substituted with one or more halogen atoms ;
-R ₁ and R ₂ together with the carbon atom carrying them may form a C ₃ -C ₇ cycloalkyl group;
-R ₃ represents a hydrogen atom;
-R ₄ are substituted by C ₃ -C ₇ cycloalkyl group optionally, C ₁ -C ₆ alkyl, (CH _{2) n} OR ₆ group, C ₃ -C ₇ cycloalkyl group or a C ₁ -C ₆ Represents a group selected from alkyl groups;
-R ₅ represents a group selected from hydrogen atom or a C ₁ -C ₆ alkyl group;
-R ₆ represents a group selected from hydrogen atom or a C ₁ -C ₆ alkyl group;
-N is 1, 2 or 3] in the form of a base or acid addition salt. A compound of formula (I) according to claim 1 in the form of a base or acid addition salt, characterized in that W represents a nitrogen atom. Y is equal to or representing the C ₂ -C ₃ alkynylene group, the compound of formula (I) according to claim 1 or 2 in the form of a base or an acid addition salt. A compound of formula (I) according to any one of claims 1 to 3 in the form of a base or acid addition salt, characterized in that Y represents an ethynylene group. -Z represents a bond or a CR ₁ R ₂ group;
-R ₁ is a group selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a (CH ₂ ) _n OR ₆ group, a C ₃ -C ₇ cycloalkyl group, an aryl group, or a 5- or 6-membered heteroaryl group. Representation;
-R ₂ represents a group selected from hydrogen atom, C ₁ -C ₆ alkyl or trifluoromethyl groups;
Represents a group -R ₆ are selected from hydrogen atom or a C ₁ -C ₆ alkyl group;
5. A compound of formula (I) according to any one of claims 1 to 4 in the form of a base or acid addition salt, characterized in that -n is 1, 2 or 3. -Z represents a CR ₁ R ₂ group;
-R ₁ is a group selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a (CH ₂ ) _n OR ₆ group, a C ₃ -C ₇ cycloalkyl group, an aryl group, or a 5- or 6-membered heteroaryl group. Representation;
-R ₂ represents a group selected from hydrogen atom, C ₁ -C ₆ alkyl or trifluoromethyl groups;
Represents a group -R ₆ are selected from hydrogen atom or a C ₁ -C ₆ alkyl group;
6. A compound of formula (I) according to any one of claims 1 to 5 in the form of a base or acid addition salt, characterized in that -n is 1, 2 or 3. R ₄ is characterized to represent a C ₁ -C ₆ alkyl group, compounds of formula (I) according to any one of claims 1 in the form of a base or an acid addition salt 6. R _Four 8. A compound of formula (I) according to any one of claims 1 to 7 in the form of a base or acid addition salt, characterized in that represents an ethyl group. R ₅ is characterized in that a hydrogen atom, a compound of formula (I) according to any one of claims 1 in the form of a base or an acid addition salt 8. -W represents a nitrogen atom or a CH group;
-Y is optionally substituted with R ₇ represents a halogen atom, a C ₂ -C ₃ alkynylene group or a 1,4-phenylene group;
-Z represents a bond or a CR ₁ R ₂ group;
-R ₁ is a group selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a (CH ₂ ) _n OR ₆ group, a C ₃ -C ₇ cycloalkyl group, an aryl group, or a 5-membered or 6-membered heteroaryl group An aryl group or a 5- or 6-membered heteroaryl group is optionally substituted with a halogen atom ;
-R ₂ represents a group selected from hydrogen atom, C ₁ -C ₆ alkyl or trifluoromethyl groups;
-R ₃ is hydrogen;
-R ₄ is substituted with a C ₃ -C ₇ cycloalkyl group optionally, C ₁ -C ₆ alkyl, (CH _{2) n} OR ₆ group, C ₃ -C ₇ cycloalkyl group or a C ₁ -C ₆ Represents a group selected from alkyl groups;
-R ₅ are radicals represents a group selected from hydrogen atom or a C ₁ -C ₆ alkyl group;
Represents a group -R ₆ are selected from hydrogen atom or a C ₁ -C ₆ alkyl group;
10. A compound of formula (I) according to any one of claims 1 to 9 in the form of a base or acid addition salt, characterized in that -n is 1, 2 or 3. R ₁ and R ₂ and forming a C ₃ -C ₇ cycloalkyl group together with the carbon atom carrying them, claim 1 in the form of a base or an acid addition salt 10 A compound of formula (I) according to any one of the above. 2-Amino-1-ethyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 Naphthyridin-4-one,
2-Amino-1-propyl-7-((3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8 Naphthyridin-4-one,
2-Amino-7- (3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one ,
2-Amino-1-ethyl-7- (3-hydroxy-3-pyridin-2-ylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine-4 -On,
2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl] -3- (4-methyl-1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1- (cyclopropylmethyl) -7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7-[(3R) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl] -3- (1H-imidazol-2-yl) -1H-quinoline-4- on,
2-amino-7- (3-chloro-4-hydroxyphenyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7- [3- (2-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine -4-one,
2-amino-1-cyclopentyl-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1- (3-methoxypropyl) -1H- [1,8] naphthyridin-4-one ,
2-Amino-7- (3-hydroxypent-1-ynyl) -3- (1H-imidazol-2-yl) -1- (2-methoxyethyl) -1H- [1,8] naphthyridin-4-one ,
2-amino-1-ethyl-7-[(1-hydroxycyclobutyl) ethynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7-[(1-hydroxycyclopentyl) ethynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-methylpent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-phenylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7- [3- (3-fluorophenyl) -3-hydroxybut-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridine -4-one,
2-Amino-1-ethyl-3- (1H-imidazol-2-yl) -7- (4,4,4-trifluoro-3-hydroxy-3-phenylbut-1-ynyl) -1H- [1 , 8] naphthyridin-4-one,
2-Amino-7- (3-cyclopropyl-3-hydroxybut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one ,
2-Amino-1-ethyl-7- [3-hydroxy-3- (thiophen-2-yl) but-1-ynyl] -3- (1H-imidazol-2-yl) -1H- [1,8] Naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxybut-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-1-ethyl-7- (3-hydroxypent-1-ynyl) -3- (1H-
Imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-hex-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-4-methylpent-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-amino-1-ethyl-7- (3-hydroxy-3-phenylprop-1-ynyl) -3- (1H-imidazol-2-yl) -1H- [1,8] naphthyridin-4-one,
2-Amino-7-((3R) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -on,
2-Amino-7-((3S) -3,4-dihydroxy-3-methylbut-1-ynyl) -1-ethyl-3- (1H-imidazol-2-yl) -1,8-naphthyridine-4 ( 1H) -on,
2-Amino-1-ethyl-7-((3S) -3-hydroxy-4-methoxy-3-methylbut-1-ynyl) -3- (1H-imidazol-2-yl) -1,8-naphthyridine 2. A compound of formula (I) according to claim 1 selected from 4 (1H) -one. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 12 , comprising formula (VII):

Wherein X is chlorine or bromine, and R ₄ and R ₅ are as defined for general formula (I) as defined in any one of claims 1 to 12 ]. XVa):

Reacting with a compound of the formula wherein R ₁ , R ₂ and R ₃ are as defined for general formula (I) as defined in any one of claims 1 to 12 ;
Or general formula (XVb):

Reacting with a compound of the formula wherein R ₃ and R ₇ are as defined for general formula (I) according to any one of claims 1 to 12 ;
A process characterized by carrying out a normal deprotection step before or after reacting a compound of formula (VII) with a compound of general formula (XVa) or a compound of general formula (XVb). A medicament comprising a compound of formula (I) according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer, or a mixture thereof. 13. A compound according to any one of claims 1 to 12 , or a pharmaceutically acceptable salt, or enantiomer or diastereomer, or mixture thereof, and at least one pharmaceutically acceptable enhancer. A pharmaceutical composition comprising a dosage form. A compound of formula (I) according to any one of claims 1 to 12 , and
An alkylating agent,
-Intercalating agents,
-An anti-microtubule agent,
An antimitotic agent,
An antimetabolite,
An antiproliferative agent,
-Antibiotics,
An immunomodulator,
-Anti-inflammatory agents,
A kinase inhibitor,
-Anti-angiogenic agents,
-A vascular therapeutic agent,
-A pharmaceutical composition comprising at least one therapeutic agent selected from female and male hormones. 13. A compound of formula (I) according to any one of claims 1 to 12 for use in the manufacture of a medicament for the prevention and / or treatment of diseases involving VEGFR-3. 13. A compound of formula (I) according to any one of claims 1 to 12 for use in the manufacture of a medicament for the prevention and / or treatment of cancer and metastasis. Glioblastoma, multiple myeloma, myelodysplastic syndrome, Kaposi's sarcoma, cutaneous hemangiosarcoma, solid tumor, lymphoma, melanoma, breast cancer, colorectal cancer, lung cancer including non-small cell cancer, pancreatic cancer, prostate cancer, In the manufacture of a medicament for the prevention and / or treatment of kidney cancer, head and neck cancer, liver cancer, ovarian cancer, airway and breast cancer, or other tumors that express VEGFR-3 or involve angiogenesis or lymphangiogenesis processes 13. A compound of formula (I) according to any one of claims 1 to 12 for use. Formula (I) according to any one of claims 1 to 12 , for use in the manufacture of a medicament for the prevention and / or treatment of non-cancerous proliferative diseases or pathological angiogenesis associated with VEGFR-3. Compound. Arthropathy, restenosis, psoriasis, hemangioma, lymphangioma, glaucoma, glomerulonephritis, diabetic nephropathy, nephrosclerosis, thrombotic microangiopathies syndrome, cirrhosis, atherosclerosis, organ transplant rejection, or for the prevention and / or use in the manufacture of a medicament for the treatment of diseases from ocular diseases associated with angiogenesis or lymphangiogenesis process is selected from the group consisting, according to an item any of claims 1 to 12 Of the formula (I) Formula (I) according to any one of claims 1 to 12 , for use in the manufacture of a medicament for the prevention and / or treatment of autoimmune diseases such as chronic or non-chronic inflammation, microbial infections and rheumatoid arthritis. ). 13. A compound of formula (I) according to any one of claims 1 to 12 for use in the manufacture of a medicament for the prevention and / or treatment of rare diseases such as lymphangioleiomyomatosis and Gorham disease.